Mental retardation (MR) is the most common cause of handicaps in children and young adults and accounts for 2-3% in the general population. Patients with MR often require long-term medical and supportive care or services and accumulate enormous costs and burden to the families and the society. The average lifetime costs per person with MR were estimated to be more than $1 million. X-linked mental retardation (XLMR) occurs in 1 in 600 males and is genetically heterogeneous. Among the >150-200 responsible loci on the X chromosome, <60 genes have been cloned. Identification of XLMR genes is essential for diagnosis, counseling, prevention, patient management, and rational development of effective therapy. It will also provide insight into the mechanism of human cognitive function. Our long-term goals are to understand the molecular basis and mechanism of X-linked mental retardation. In this application, we wish to capitalize on the exciting results from our pilot study of using a human X chromosome cDNA microarray (XCM) to identify novel XLMR genes. This XCM will be used to screen RNA from lymphoblasts of XLMR males to identify genes that show significant alternations in transcript levels. This strategy is based on the fact that a fraction of the mutations (estimated to be >30%) at any given locus result in dramatic alternations in the abundance of steady state transcripts. This approach is designed to detect mutations that result in a change in the abundance of mRNA due to mechanism such as promoter mutations, gene deletions or duplications, and abnormal RNA splicing associated with frameshift mutation and nonsense mutations associated with nonsense-mediated mRNA. It carries the advantage of fast screening of genes on the entire X chromosome without the need for large pedigree. Specifically we will (1) use XCM to screen 120 lymphoblast cell lines from XLMR males to identify novel candidate genes (2) identify responsible genetic defects by sequencing of the novel candidate genes in proband and in a large collection of XLMR males (3) functional studies of 4-6 novel XLMR genes to understand their physiological roles in human congnition and how mutations in these gene cause mental retardation. Results of the study will help to advance our knowledge on the genetic causes of mental retardation and to develop rational strategies for diagnosis, genetic counseling, prevention, and clinical care of patients with impairment of cognitive function..